I have recently joined the faculty of the Psychiatry department at Washington University and am in the process of establishing my own independent research group working on the molecular genetics of Alzheimer's disease (AD). During the last six years I have successfully used a genetic approach to identify mutations at codon 717 of the amyloid precursor protein gene in some cases of familial Alzheimer's disease (FAD). In the intermediate term, my goal is to continue to use a this approach to unravel the causes of FAD and other familial dementias which show Mendelian transmission. In the longer term I plan to use a similar approach to study other psychiatric disorders which exhibit familial clustering but do not show Mendelian inheritance, such as alcoholism and schizophrenia. Receiving a career development award will make a substantial difference to me as I am expected to raise 95% of my salary from grant support. This award would give me a stable source of support which would allow me devote my full attention to the research rather then spending a substantial amount of time writing grants to support my salary and will also permit me the discretion to elect to assume only those teaching and/or administrative duties I wish. I have a tenure track associate professor position jointly held between the Departments of Psychiatry and Genetics. Within the Psychiatry department there are a substantial number of faculty who share my interest in the genetics of psychiatric disorders, whilst in other departments within the medical school there are many people who share my interest in molecular genetics and in transgenic approaches to the study of inherited diseases and gene expression and regulation. Finally, there are many faculty throughout the medical school who are part of the Alzheimer's Disease Research Center and who contribute to a co-ordinate multidisciplinary approach to understanding the pathogenesis of Alzheimer's. My principal research interest is understanding the pathogenesis of AD. We are testing the hypothesis that mutations in the amyloid precursor protein (APP) gene can cause AD. To test this hypothesis we are introducing the APP717 mutations into mice via homologus recombination in embryonic stem cells to determine whether they are sufficient to cause disease. In addition we are collaborating with Dr. Frank Ashall who is using cell lines derived from patients with the APP717 mutations to determine the biochemical effect to these mutations upon the regulation of APP expression and proteolytic processing. Secondly, we are using positional cloning to identify the gene on chromosome 14 which predisposes to another form of early onset FAD. Thirdly, we are doing an association study with samples from control and AD individuals to determine whether alleles of the association study with samples from control and AD individuals to determine whether alleles of the APP gene may predispose to AD in the elderly. It is hoped that these studies will help to determine whether premature b-amyloid deposition is central to the pathogenesis of all cases of AD or only those which are caused by mutations within the APP gene.